A physiologically active low-molecular weight hydrophobic substance such as a steroid hormone shows its activities as a ligand through its specific nuclear receptor. The nuclear steroid hormone receptors constitute a gene superfamily and the receptors work as a ligand-dependent transcription factor and hence regulate (activate or inhibit) the expression of the target genes at the level of transcription. Such receptors include mineralocorticoid receptor (MR), glucocorticoid receptor (GR), androgen receptor (AR), estrogen receptor (ER) and progesterone receptor (PR). The ligand of said steroid hormone receptors, e.g., a mineralocorticoid (aldosterone) or a glucocorticoid (cortisol and the like) exhibits various physiological activities via respective receptor (Journal of Endocrinology, 2001; 169: p. 437-445).
MR-specific ligand, aldosterone, is one of mediators in renin-angiotensin-aldosterone system (RAAS). Formerly, aldosterone has been considered to be nothing but a hormone which is produced only in adrenal glands and acts on distal urinary tubule to regulate water and sodium metabolism. However, recent studies proved that aldosterone is produced in various tissues such as heart, blood vessels, brain and the like and its receptors are widely distributed in cardiovascular tissues and the like. Besides, aldosterone is not only a risk hormone showing various impeding effects (e.g., cardiac fibrosis/necrosis, potentiation of catecholamine activity, deterioration of baroreceptor response). In the recent large scale clinical trials (RALES and EPHESUS), it was confirmed that the concomitant use of an aldosterone receptor antagonist (eplerenone or spironolactone) with a conventional medicament such as an ACE inhibitor and the like significantly reduced hospitalization and mortality rate in patients with severe heart failure and significantly ameliorate the prognosis of patients with acute cardiac infarction (New England Journal of Medicine, 2003; 341: p. 709-717, New England Journal of Medicine, 2003; 348: p. 1309-1321). In this regard, it is considered that effective blockade of such hormone is important to establish the therapy of the cardiovascular diseases associated with aldosterone and its receptors.
As mentioned above, any ligands having an affinity to MR and activity of modulating the receptor function, namely repressors, antagonists, agonists, partial antagonists or partial agonists, may be useful as medicaments for prevention or treatment of the diseases or disease states associated with aldosterone. On the other hand, a steroidal MR-ligand such as spironolactone or eplerenone has been often associated with specific and serious side effects (e.g., gynecomastia, irregular menses, erectile dysfunction), and therefore it has been desired to develop a compound having safety as a medicament without such side effects.
Up to now, 6H-dibenzo[b,e]oxepine derivatives (WO2005/066161), dihydro-pyridine derivatives (WO2005/097118), dibenzo[b,d]pyrane derivatives (Bioorganic and Medicinal Chemistry Letters, 2004; 14: p. 2079-2082) and the like have been known as a non-steroidal ligand having an affinity to MR. However, no benzoxazine-sulfonamide derivative having MR-modulating activity (e.g., MR-antagonizing activity) has been reported. On the other hand, some benzoxazine-sulfonamide derivatives have been disclosed in the following references (WO97/017333, EP432893A, WO2001/057003, WO99/000371).